title: Patulin induces pro-survival functions via autophagy inhibition and p62 accumulation.
abstract: Patulin (PAT) is one of the most common mycotoxins found in moldy fruits. Skin contact is one of the most likely exposure routes of PAT. Investigation of dermal toxicity of PAT is clearly needed and has been highlighted by WHO. In the present study, using human keratinocyte HaCaT cells as a model, we found that treatment with PAT caused an increased autophagosome accumulation. Measurements of autophagic flux demonstrated that the accumulation of autophagosomes by PAT was not directly due to enhanced autophagosome formation but due to inhibition of autophagosome degradation. Reductions in the activities of the lysosomal enzymes cathepsin B and cathepsin D by PAT might contribute to this inhibitory effect. Consistent with this, inhibition of autophagosome degradation by PAT resulted in accumulation of p62 that functioned as a pro-survival signal. The pro-survival function of p62 was found to be attributed to reactive oxygen species-mediated cytoprotective endoplasmic reticulum (ER) stress response. ER stress exerted cytoprotective effect via extracellular signal-regulated kinase1/2-dependent B-cell CLL/lymphoma 2-associated agonist of cell death inhibitory phosphorylation. Given the critical role of autophagy and its substrate p62 in carcinogenesis, our findings may have important implications in PAT-induced skin carcinogenesis.
authors.affiliation: 1] Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China [2] Laboratory of Food Engineering and Nutrition Research, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Science, Qingdao, China.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.forename: S
authors.initials: S
authors.lastname: Yin
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Huo
authors.forename: L
authors.initials: L
authors.lastname: Fan
authors.forename: H
authors.initials: H
authors.lastname: Hu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology; D008954:Models, Biological; D010365:Patulin / Q000494:pharmacology*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018942:Macrolides; D017382:Reactive Oxygen Species; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D051025:bcl-Associated Death Protein; C040929:bafilomycin A1; D010365:Patulin; D048049:Extracellular Signal-Regulated MAP Kinases; D002401:Cathepsin B; D002402:Cathepsin D